Pd-Catalyzed Sequential C–C Bond Formation and Cleavage

Zhi-Quan Lei , Fei Pan , Hu Li , Yang Li , Xi-Sha Zhang , Kang Chen , Xin Wang .... So Won Youn , So Ra Lee , Yun Ah Kim , Da Young Kang , Min Jung Ja...
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Pd-Catalyzed Sequential C−C Bond Formation and Cleavage: Evidence for an Unexpected Generation of Arylpalladium(II) Species So Won Youn,* Byung Seok Kim, and Arun R. Jagdale Department of Chemistry and Research Institute for Natural Sciences, Hanyang University, Seoul 133-791, Korea S Supporting Information *

Scheme 1. Transition-Metal-Mediated Cyclization of 2Alkenylphenyl Carbonyl Compounds

ABSTRACT: A Pd(II)-catalyzed reaction engaging alkenyl β-keto esters is reported that leads to the formation of 1naphthols and an unexpected generation of arylpalladium(II) species. Interception of the in situ generated arylpalladium(II) species in a Mizoroki−Heck reaction, together with additional mechanistic studies, provided strong evidence in support of the first aromatization-driven β-carbon elimination process. A single Pd catalyst served to promote a series of both C−C bond forming and cleavage events in an unprecedented manner.

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ransition-metal-catalyzed transformations involving the cleavage of chemically inert C−H1 and C−C2,3 bonds have received widespread recent attention from the synthetic community. The latter transformations, generally more challenging, have been achieved primarily through oxidative insertion of a transition metal into the C−C bond or β-carbon elimination3 of a carbon−metal (i.e., M-C-C-C) or heteroatom−metal species (e.g., M-O-C-C). β-Hydride elimination is often a preferred competing pathway over β-carbon elimination, where the driving force to facilitate the latter process usually invokes the release of ring strain or the formation of a relatively more stable intermediate (such as a πallylmetal intermediate). As such, programmed β-carbon elimination and its potential in organic synthesis remain a challenging area yet to be explored. As part of our continued interest in transition-metalmediated C−C bond-forming processes, we recently disclosed a Au(I)-catalyzed cyclization of 2-alkenylphenyl carbonyl compounds to afford a variety of indenes, indenols, indanones, and naphthalenes (Scheme 1a).4 Early on, we systematically examined various transition metals, and much to our surprise, an unexpected formation of 1-naphthol 2a was observed when 2-alkenylphenyl β-keto ester 1aa was exposed to a catalytic amount of Pd(II) under oxidative conditions (Scheme 1b).5−7 Indeed, on cursory inspection of the skeletal framework of the substrate (1aa) and the observed 1-naphthol product (2a), we realized the pendent phenyl group of the stilbene starting material had been cleaved during this process. Recognizing the novelty of this process in generating 1-naphthol derivatives, and more intriguingly, the origin of the unexpected C−C bond scission, here we report the findings of our methodological and mechanistic investigations. We began using 1aa as the test substrate and soon identified Pd(O2CCF3)2−Cu(OAc)2 as the most effective Pd(II)− oxidant combination; no reaction was observed in the absence © XXXX American Chemical Society

of either one of these reagents.8 The use of base or ligand as additives did not improve the production of 2a, and the addition of BHT or ascorbic acid had no deleterious effect on the reaction, which excludes the presence of propagating radical species. Ultimately, the use of 5 mol % Pd(O2CCF3)2 and 2 equiv of Cu(OAc)2 in ClCH2CH2Cl (or dioxane) at 100 °C was identified as the optimal reaction protocol, and the reaction could be performed without strict exclusion of moisture and air. The established reaction parameters proved generally effective for a wide variety of substrates, as shown in Table 1. Substrates bearing substituted phenyl rings at R5 were well-tolerated, with little electronic dependence, whereas R5 = alkyl afforded only trace amount of the 1-naphthol product (entries 1−10). β-Keto esters bearing alkoxy substituents (entries 12−15) and 1,3diketones (entries 16 and 17) were all competent substrates, apart from diaryl 1,3-diketone 1ha. Allylic substrates 1lb and 1ma also cyclized smoothly to afford 1-naphthols 2l and 2m, respectively (entries 24 and 25), but trisubstituted stilbene 1la was unsuccessful in this reaction (entry 23). Having established a workable condition for the conversion of 2-alkenylphenyl β-keto esters (and 1,3-diketones) to the 1naphthol products, we next pursued in earnest the investigation of the unexpected C−C bond cleavage. As an entry point to this study, and because the conversion from 1 to 2 was generally modest, we set out to account for the mass balance through a series of detailed 1H NMR and GC-MS analyses, together with the isolation of side products. We identified Received: February 17, 2012

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compounds 1aa′, 3aa, 3aa′, and 4aa as the principal byproducts in the reaction of 1aa (Figure 1). 1aa′ and 3aa′ (and 4aa, vide inf ra) were of particular interest due to the incorporation of an additional phenyl group (similar results were obtained for reactions with 1ae, 1af, and 1ag8).

Table 1. Pd-Catalyzed Synthesis of Various 1-Naphthols 2 from Alkenyl 1,3-Dicarbonyl Compounds 1a

Figure 1. Major side products observed in the reaction of 1aa.

While a clear mechanistic picture was elusive at this juncture, we hypothesized the incorporation of an additional phenyl group could invoke the participation of an Ar−M species generated in the reaction mixture. We further questioned if this Ar−M species could be intercepted with the introduction of a suitable electrophile. To our delight, when methyl acrylate was introduced to our standard reaction conditions using 1aa as the substrate, cinnamate 5aa was obtained in 58% yield, alongside the previously described 2aa (63%, Table 2, entry 1). Depending on the 2-alkenylphenyl β-keto ester substrate, different substituted methyl cinnamates could be obtained in respectable yields (entries 1−12). Methyl acrylate could also be replaced with a diverse array of activated olefins (entries 13− 21) and styrenes (entries 22−27). With the successful identification of cinnamate and stilbene derivatives 5, the involvement of an Ar−M species seems highly plausible. The presence of an Ar−M species (M = Pd) was deemed most likely, since its participation in the Mizoroki− Heck-type cross-coupling9 with various activated and nonactivated olefins is well-precedented. A plausible mechanistic proposal is presented in Scheme 2. We speculate that the O,O′bound complex A, formed initially upon treatment of 1 with Pd(II), first undergoes rearrangement to afford the alkenecoordinated C-bound tautomer B,10 which then engages in a syn carbopalladation across the stilbene olefin to generate transient intermediate C with concomitant C−C bond formation (B→C). At this point, intermediate C, with synorientated Pd and Ar substituents, is poised to undergo βcarbon elimination, leading to the generation of arylpalladium species D. We also speculate that, further to the prerequisite syn stereochemical arrangement of the Pd and Ar substituents in C, the formation of 1-naphthol (2) through aromatization provides an additional and essential driving force to facilitate the β-carbon elimination.11 Carbopalladation of the external olefin with the newly generated arylpalladium species D in a Mizoroki−Heck manner affords the cross-coupling product 5, where the soliberated Pd(0) is reoxidized to Pd(II) with the aid of Cu(OAc)2. Several additional experiments and analysis provided further support for this mechanistic proposal. First, with the speculated arylpalladium species D in mind, several attempts to intercept and subsequently isolate the arylpalladium complex by the addition of amino or phosphino ligands proved unrewarding. Reaction of (Z)-1aa under the same reaction conditions failed to deliver any product 2a. Although 2a′ could be speculated as the possible product resulting from the alternative β-hydride elimination pathway, we believe there is a significant energy barrier that prevents the cis-stilbene olefin from being in close enough proximity for the reaction to take place (B′, Scheme

a Reaction conditions: 1 (1 equiv), Pd(O2CCF3)2 (5 mol %), and Cu(OAc)2 (2 equiv) in ClCH2CH2Cl or dioxane at 100 °C. bIsolated yields. cIn ClCH2CH2Cl (0.025 M). dIn dioxane (0.1 M).

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Table 2. Pd-Catalyzed Reactions of Aryl-Substituted Alkenyl β-Keto Esters 1 with Olefinsa

Scheme 2. Proposed Mechanism

Scheme 3. Reactions of (Z)-1aa and 1aa in the Presence of CuCl2

As alluded to earlier, reaction of 1aa afforded 1aa′ and 3aa′ as the primary side products in addition to 1-naphthol 2a. Mechanistically, the formation of 1aa′ and 3aa′ can now be easily rationalized through a Mizoroki−Heck reaction engaging arylpalladium species D and 1aa and subsequent decarboxylation (or through decarboxylated 3aa and its Mizoroki−Heck reaction with D), respectively (Scheme 4a). Crossover experiments between 1aa and 1ae afforded the byproduct mixture containing all the possible combinations, which further supports the generation of Ar−Pd (D, and Ar′−Pd) during the reaction (Scheme 4b). Pd-mediated oxidative cleavage of substituted stilbene (i.e., 1aa′ or 3aa′) has also been reported,12 and has been validated by us experimentally (4aa, Scheme 4a). Finally, in the competition experiments between alkenyl βketo esters with varying substituents on the departing aryl ring (1aa, 1ac, 1af, 1ag), electron-rich substrates generally proceeded significantly faster than their electron-deficient Scheme 4. Formation of Side Products and Crossover Experiments

a Reaction conditions: 1 (1 equiv), olefin (2 equiv), Pd(O2CCF3)2 (5 mol %), and Cu(OAc)2 (2 equiv) in ClCH2CH2Cl (0.05 M) at 100 °C. bIsolated yields. c3 equiv of olefin. d1.5 equiv of olefin. e10 mol % Pd(O 2 CCF 3 ) 2 . f 5 equiv of olefin. g Internal olefin and the corresponding exo olefin isomer were obtained in 28% and 17% yields, respectively. hThe inseparable mixture of internal olefin and the corresponding exo olefin isomer was obtained in 48% yield and a ratio of 42:58, determined by 1H NMR. i2a and 5cc were not separable; therefore, each yield was calculated from both the weight of the purified mixture of 2a and 5cc and their ratio, determined by 1H NMR.

3a). The same steric argument could also account for the failure of substrate 1la in this reaction. Interestingly, reaction of 1aa in the presence of CuCl2 instead of Cu(OAc)2 gave a 3-phenylsubstituted 1-naphthol (2a′) as a sole product, which suggests a contrasting outer-sphere anti carbopalladation pathway through the in situ generated PdCl2 (Scheme 3b).5c,6a,b C

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Seoul National University) for helpful discussions and valuable suggestions as well as editorial assistance.

counterparts (Table 3). This electronic dependence is in agreement with the migratory aptitude of the aryl group during

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Table 3. Competition Experiments of 4′-Substituted ArylContaining Alkenyl β-Keto Esters 1

(1) Selected recent reviews on C−H activation: (a) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (b) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (c) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (d) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (2) Selected reviews on C−C activation: (a) Murakami, M.; Matsuda, T. Chem. Commun. 2011, 47, 1100. (b) Bonesi, S. M.; Fagnoni, M. Chem.Eur. J. 2010, 16, 13572. (c) Seiser, T.; Cramer, N. Org. Biomol. Chem. 2009, 7, 2835. (d) Necas, D.; Kotora, M. Curr. Org. Chem. 2007, 11, 1566. (e) Jun, C.-H. Chem. Soc. Rev. 2004, 33, 610. (f) Mitsudo, T.; Kondo, T. Synlett 2001, 309. (g) Murakami, M.; Ito, Y. Top. Organomet. Chem. 1999, 3, 97. (h) Rybtchinski, B.; Milstein, D. Angew. Chem., Int. Ed. 1999, 38, 870. (3) Reviews on β-carbon elimination: (a) Aïssa, C. Synthesis 2011, 3389. (b) Murakami, M.; Makino, M.; Ashida, S.; Matsuda, T. Bull. Chem. Soc. Jpn. 2006, 79, 1315. (c) Satoh, T.; Miura, M. Top. Organomet. Chem. 2005, 14, 1. A selected example: (d) Terao, Y.; Wakui, H.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem. Soc. 2001, 123, 10407. (4) (a) Jagdale, A. R.; Youn, S. W. Eur. J. Org. Chem. 2011, 3904. (b) Jagdale, A. R.; Park, J. H.; Youn, S. W. J. Org. Chem. 2011, 76, 7204. (5) Transition-metal-catalyzed intramolecular addition of 1,3dicarbonyl compounds to alkenes: (a) Zhou, C.-Y.; Che, C.-M. J. Am. Chem. Soc. 2007, 129, 5828. (b) Pei, T.; Widenhoefer, R. A. J. Am. Chem. Soc. 2001, 123, 11290. (c) Qian, H.; Widenhoefer, R. A. J. Am. Chem. Soc. 2003, 125, 2056. Intermolecular addition of 1,3-dicarbonyl compounds to alkenes: (d) Cucciolito, M. E.; D’Amora, A.; Vitagliano, A. Organometallics 2010, 29, 5878. (e) Li, Y.; Yu, Z.; Wu, S. J. Org. Chem. 2008, 73, 5647. (f) Nguyen, R.-V.; Yao, X.-Q.; Bohle, D. S.; Li, C.-J. Org. Lett. 2005, 7, 673. (g) Yao, X.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 6884. (6) Pd-catalyzed oxidative cyclization of alkenyl 1,3-dicarbonyl compounds involving β-hydride elimination: (a) Han, X.; Widenhoefer, R. A. J. Org. Chem. 2004, 69, 1738. (b) Pei, T.; Wang, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2003, 125, 648. (c) Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778. (d) Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem., Int. Ed. 2003, 42, 2892. (7) (a) Pd-catalyzed intra- and intermolecular allylic alkylation between 1,3-dicarbonyls and alkenes: Lin, S.; Song, C.-X.; Cai, G.-X.; Wang, W.-H.; Shi, Z.-J. J. Am. Chem. Soc. 2008, 130, 12901. (b) Selenium-mediated cyclization of alkenyl β-keto esters 1 in the presence of the Lewis acid FeCl3 for the synthesis of naphthols through 1,2-rearrangement of aryl groups: Shahzad, S. A.; Vivant, C.; Wirth, T. Org. Lett. 2010, 12, 1364. (8) For details, see the Supporting Information. (9) Reviews on the Mizoroki−Heck reaction: (a) Heck, R. F. Acc. Chem. Res. 1979, 12, 146. (b) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009. (10) Related examples of Pd enolates: (a) Ito, Y.; Aoyama, H.; Hirao, T.; Mochizuki, A.; Saegusa, T. J. Am. Chem. Soc. 1979, 101, 494. (b) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234. (c) Chernyak, N.; Gorelsky, S. I.; Gevorgyan, V. Angew. Chem., Int. Ed. 2011, 50, 2342. (d) Metz, A. E.; Berritt, S.; Dreher, S. D.; Kozlowski, M. C. Org. Lett. 2012, 14, 760. (11) Related examples of aromatization-driven C−C bond cleavage: (a) Crabtree, R. H.; Dion, R. P.; Gibboni, D. J.; McGrath, D. V.; Holt, E. M. J. Am. Chem. Soc. 1986, 108, 7222. (b) Halcrow, M. A.; Urbanos, F.; Chaudret, B. Organometallics 1993, 12, 955. (12) Wang, A.; Jiang, H. J. Org. Chem. 2010, 75, 2321.

a

Isolated yields of each recovered starting material (1A and 1B) and products (5A and 5B) based on amount used of 1A or 1B. bIsolated yield of 2a and mass balance based on total amount of 1A and 1B. c First and second mass balances based on the amount of recovered 1A/1B, byproduct (if any), and products either 2a or 5A/5B, respectively. dFor 6 h. eDecarboxylated byproduct 3aa obtained in 7% isolated yield based on the amount used of 1aa. fDecarboxylated byproduct 3ag obtained in 6% isolated yield based on the amount used of 1ag.

the β-carbon elimination. Furthermore, the β-carbon elimination is expected to take place much more effectively for M− C−C−C(sp2) species than M−C−C−C(sp3) species (cf. substrates 1ai and 1aj). In summary, we have developed a novel and concurrent preparation of 1-naphthols and cinnamate/stilbene derivatives through a Pd(II)-catalyzed reaction of 2-alkenylphenyl β-keto esters and 1,3-diketones with olefins. More significantly, we have uncovered an unprecedented catalytic process that operates through a unique mode of C−C bond activation. A single catalytic system enabled intramolecular C−C bond formation through inner-sphere syn carbopalladation, C−C bond cleavage via a novel aromatization-driven syn β-carbon elimination followed by intermolecular C−C bond formation in a Mizoroki−Heck manner. These new findings may expand the current understanding of Pd(II) reactivity and present new opportunities to broaden the current lexicon of Pd(II)catalyzed (cascade) transformations. Further investigations to expand this concept together with detailed mechanistic studies are currently underway in our laboratory.

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ASSOCIATED CONTENT

S Supporting Information *

Full experimental details and characterization data. This material is available free of charge via the Internet at http:// pubs.acs.org.

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

[email protected] Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (Nos. 2011-0003705 and 2012-0002223). We sincerely thank Professor David Yu-Kai Chen (Department of Chemistry, D

dx.doi.org/10.1021/ja304616q | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX